1. Field of the Invention
The present invention is directed to new carbapenem antibiotics in which the 2-substituent has the formula ##STR2## wherein A is C.sub.2 -C.sub.6 straight or branched chain alkylene and R.sup.10 and R.sup.11 each independently represent optionally substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, heterocyclyl, heterocyclyl-aliphatic, heteroaryl or heteroar-aliphatic radicals, or R.sup.10 and R.sup.11 when taking together with the EQU S.sup..sym.
to which they are attached represent an optionally substituted sulfur-containing heterocyclic ring.
2. Description of the Prior Art
A number of .beta.-lactam derivatives containing the carbapenem nucleus ##STR3## have been disclosed in the literature. These carbapenem derivatives have been reported to possess utility as antibacterial agents and/or .beta.-lactamase inhibitors.
The initial carbapenem compounds were natural products such as thienamycin of the formula ##STR4## obtained by fermentation of Streptomyces cattleya (U.S. Pat. No. 3,950,357). Thienamycin is an exceptionally potent broad-spectrum antibiotic which possesses notable activity against various Pseudomonas species, organisms which have been notoriously resistant to .beta.-lactam antibiotics.
Carbapenems of the general formula ##STR5## wherein R.sup.1 is H or acyl and R.sup.8 is H or substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, aryl, aralkyl, aralkenyl, aralkynyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl, are disclosed in U.S. Pat. No. 4,218,463. There is no disclosure of any R.sup.8 substituents of the type ##STR6## in which A is alkylene.
Compounds of the formula ##STR7## wherein R.sup.5, R.sup.6 and R.sup.7 are independently selected from H and substituted or unsubstituted: alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl are disclosed in U.S. Pat. No. 4,235,920. Among the compounds disclosed in U.S. Pat. No. 4,235,920 is ##STR8## wherein A is a pharmaceutical acceptable anion. The above-mentioned quaternary amine derivative is also described in Recent Advances in Chemistry of .beta.-Lactam Antibiotics, Royal Society of Chemistry, London, 1981, pg 240-254, where its antibacterial activity on average is reported as approximately 1/2 to 2/3 that of thienamycin.
Compounds of the formula ##STR9## wherein ##STR10## attached to the amino nitrogen group of thienamycin represents a mono- or polycyclic N-containing heterocyclic group and R is H, substituted or unsubstituted: alkyl, aryl, alkenyl, heterocyclyalkenyl, aralkenyl, heterocyclyalkyl, aralkyl, --NR.sub.2, COOR, CONR.sub.2, --OR, or CN, are disclosed in European Patent Application 21082.
European Patent Application No. 40,408 discloses compounds of the formula ##STR11## wherein R.sup.1 is H, methyl or hydroxyl and R.sub.51 is a monovalent organic group including inter alia heterocyclicalkyl.
European Patent Application No. 38,869 discloses compounds of the formula ##STR12## wherein R.sup.6, R.sup.7, and R.sup.8 are independently selected from the group consisting of hydrogen, substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl; wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: ##STR13## wherein, relative to the above listed substituents on R.sup.6, R.sup.7, and R.sup.8, the groups R.sup.1 and R.sup.2 are independently selected from: hydrogen, alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; aryl, such as phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the aliphatic portion has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulphur atoms and wherein the alkyl moieties associated with said heterocyclic moieties have 1-6 carbon atoms. (See also European Patent Application Nos. 1627, 1628, 10317, 17992, 37080, 37081 and 37082).
European Patent Application No. 24832 discloses compounds of the formula ##STR14## wherein R.sup.1 is H or a group selected from OH, OSO.sub.3 H or a salt or C.sub.1-4 alkyl ester thereof, OR.sup.2, SR.sup.3, OCOR.sup.2, OCO.sub.2 R.sup.3 or OCONHR.sup.3, where R.sup.2 is a C.sub.1-6 alkyl group or an optionally substituted benzyl group and R.sup.3 is a C.sub.1-6 alkyl group or an optionally substituted benzyl or phenyl group and R.sup.12 is C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.3-6 alkynyl wherein the triple bond is not present on the carbon adjacent to the sulfur atom, aralkyl, C.sub.1-6 alkanoyl, aralkanoyl, aryloxyalkanoyl or arylcarbonyl, any of such R.sup.12 groups being optionally substituted, as antibacterial agents.
European Patent Application No. 38,869 mentioned above discloses synthesis of the carbapenem derivatives via intermediates of the general formula ##STR15## wherein R.sup.6 and R.sup.7 are as defined above and R.sup.2' is a readily removable carboxyl protecting group. Also disclosed as intermediates are the compounds of the formula ##STR16## wherein X is described as a leaving group.
European Patent Application No. 7973 discloses the intermediates of the formula ##STR17## where R is hydrogen or an ester group. The diazo intermediate is also disclosed in U.S. Pat. No. 4,378,315 while the keto intermediate is disclosed in U.S. Pat. No. 4,318,912.
At the Gordon Research Conference on Medicinal Chemistry held at New London, N.H. on Aug. 2-6, 1982, a handout was distributed in which a variety of carbapenem antibiotics were disclosed. Among the compounds disclosed on page 9 of the handout is the carbapenem of the formula ##STR18##
The above-mentioned carbapenem derivative is also disclosed on page 145 of European Patent Application 38869 and on page 252 of European Patent Application No. 17992.
U.S. Pat. No. 4,309,346 discloses carbapenem derivatives having 2-substituents of the formula EQU --SR.sup.8
where R.sup.8 may be inter alia heteroaralkyl in which the hetero atom or atoms in heteroaralkyl may be selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms. No disclosure is made of any sulfonium groups such as are present in the compounds of the present invention.
European Patent Application No. 74,599 discloses 5,6-cis-carbapenem derivatives of the formula ##STR19## wherein R.sup.1 is optionally substituted alkyl, cycloalkyl, cycloalkenyl, alkynyl, aryl, aralkyl or a 5 to 8 membered heterocyclic group containing 1 to 4 hetero atoms, and R.sup.2 is hydrogen or a hydroxy-protecting group. There is no disclosure, however, of compounds where R.sup.1 is ##STR20## in which A is alkylene.
European Patent Application No. 90,366 discloses carbapenem antibiotics of the formula ##STR21## wherein R.sup.1 is hydroxy, protected hydroxy or (lower)alkoxy, R.sup.2 is carboxy or protected carboxy and R.sup.3 is substituted aryl, optionally substituted pyridyl or an optionally substituted heterocyclic group containing 3-5 hetero atoms.
With respect to the 1-substituted carbapenems of the present invention, there is extensive literature disclosing carbapenems having a non-hydrogen 1-substituent and a 2-substituent similar to those disclosed in the above-mentioned references. Again, however, no art has been found teaching a 2-substituent of the type ##STR22## Examples of 1-substituted carbapenem references are indicated below.
European Patent Application No. 54,917 (equivalent to U.S. Pat. No. 4,350,631) discloses intermediates of the formula ##STR23## where R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently selected from the group consisting of hydrogen (R.sup.1 and R.sup.2 are not both hydrogen), substituted and unsubstituted: alkyl, alkenyl, and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl, and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di- and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, iodo, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms; R.sup.5 is hydrogen, salt cation, a pharmaceutically acceptable ester moiety or a removable blocking group. Also disclosed are intermediates of the formula ##STR24## where R.sup.7 is a carboxyl protecting group and R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are as defined above.
European Patent Application No. 10,317 (see also U.S. Pat. No. 4,232,036) discloses carbapenem compounds of the general formula ##STR25## where R.degree. is H or --SR.sup.8 ; R.sup.1, R.sup.6, R.sup.7 and R.sup.8 are independently selected from the group consisting of hydrogen (R.sup.1 is not H), substituted and unsubstituted: alkyl, alkenyl and alkynyl, having from 1-10 carbon atoms; cycloalkyl, cycloalkylalkyl and alkylcycloalkyl, having 3-6 carbon atoms in the cycloalkyl ring and 1-6 carbon atoms in the alkyl moieties; phenyl; aralkyl, aralkenyl, and aralkynyl wherein the aryl moiety is phenyl and the alkyl chain has 1-6 carbon atoms; heteroaryl, heteroaralkyl, heterocyclyl and heterocyclylalkyl wherein the substituent or substituents relative to the above-named radicals are selected from the group consisting of: amino, mono-, di-, and trialkylamino, hydroxyl, alkoxyl, mercapto, alkylthio, phenylthio, sulfamoyl, amidino, guanidino, nitro, chloro, bromo, fluoro, cyano and carboxy; and wherein the hetero atom or atoms in the above-named heterocyclic moieties are selected from the group consisting of 1-4 oxygen, nitrogen or sulfur atoms; and wherein the alkyl moieties of the above-recited substituents have 1-6 carbon atoms.
Despite a vast number of literature references teaching preparation of carbapenem derivatives, including derivatives having 2-substituents of the type EQU --S--A--Het,
applicant believes he is the first to prepare carbapenem derivatives having a 2-substituent wherein the alkylene group A is attached directly to a sulfonium group, i.e. a group of the type ##STR26##
Although there are a vast number of carbapenem derivatives disclosed in the literature, there is still a need for new carbapenems since known derivatives may be improved upon in terms of spectrum of activity, potency, stability and/or toxic side effects.